1. Field of the Invention
The present invention relates to a carbapenem compound which has excellent antimicrobial activity and wide range of anti-microbial spectrum, and can be administered not only as an injection but also orally. More particularly, the present invention relates to a novel carbapenem derivative which has a substituted imidazo[5,1-b]thiazole group or a salt thereof.
2. Background Art
Carbapenem derivatives, by virtue of potent antibacterial activity against a wide spectrum of bacteria, have been energetically studied as a highly useful xcex2-lactam agent, and Imipenem, Panipenem, and Meropenem have been clinically used.
Both Imipenem and Panipenem, however, are used as a mixture due to instability against renal dehydropeptidase-1 (xe2x80x9cDHP-1xe2x80x9d) in the case of Imipenem and in order to reduce nephrotoxicity in the case of Panipenem. Meropenem which has recently been marketed has a methyl group at the 1xcex2-position, so that it has increased stability to DHP-1 and thus can be used alone.
However, a need still exists for a drug having higher stability to DHP-1. Furthermore, drugs effective for methicillin resistant Staphylococcus aureus (xe2x80x9cMRSAxe2x80x9d), penicillin resistant Streptococcus pneumoneae (xe2x80x9cPRSPxe2x80x9d), resistant Pseudomonas aeruginosa and enterococci which have recently become serious problems as well as influenza have been demanded as well.
Some of the present inventors have previously reported the carbapenem derivatives having a novel heteroaromatic ring imidazo[5,1-b]thiazolium-6-ylmethyl group at the 2-position on the carbapenem ring in WO 96/028455 and the carbapenem derivatives having an imidazo[5,1-b]thiazole group through a pyrrolidinylthio group at the 2-position of the carbapenem ring in W98/023623 and, furthermore, the carbapenem derivatives having an imidazo[5,1-b]thiazole group directly at the 2-position of the carbapenem ring in WO98/032760.
Further, WO96/011932 and WO96/034868 and Japanese Patent Laid-Open Publication No. 273876/1992 disclose the carbapenem derivatives in which a carbon atom on the heteroaromatic ring is bonded to the 2-position of the carbapenem ring. However, there have been described no specifictdata on the anti-microbial activities or effectiveness for these derivatives. There have been described neither bicyclic heteroaromatic rings nor carbapenem rings having imidazo[5,1-b]thiazole group.
The present inventors have now found that novel carbapenem derivatives having a substituted imidazo[5,1-b]thiazole group at the 2-position on the carbapenem ring have high anti-microbial activities against xcex2-lactamase producing bacteria, MRSA, resistant-Pseudomonas aeruginosa, PRSP, enterococci, and influenza, and high stabilities to DHP-1. The present invention is based on such findings.
Accordingly, the object of the present invention is to provide novel compounds which have wide range of anti-gram-positive and gram-negative microbial activities, especially high anti-microbial activities against microorganisms including xcex2-lactamase producing bacteria, MRSA, enterococci, PRSP, influenza, and high stabilities to DHP-1.
According to the present invention, there is provided a compound represented by the formula (I), or a pharmacologically acceptable salt thereof or an ester at the 3-position on the carbapeem ring thereof: 
wherein
R1 represents a hydrogen atom or a methyl group,
R2, R3, R4, and R5, either one of which represents the bonding to the 2-position on the carbapenem ring, and the other three of which may be the same or different, respectively represent
a hydrogen atom,
a halogen atom,
a nitro group,
a cyano group,
a lower alkyl group which may be""substituted,
a lower cycloalkyl group which may be substituted,
a lower alkylthio group,
an arylthio group,
a C2-4 alkenyl group which may be substituted,
a formyl group,
a lower alkylcarbonyl group which may be substituted,
a lower alkoxycarbonyl group,
a lower alkylsulfonyl group,
an arylsulfonyl group which may be substituted,
an aminosulfonyl group,
an N-loweralkylaminosulfonyl group which may be substituted,
an N,N-di-lower alkylaminosulfonyl group which may be substituted,
an N-lower alkoxy-N-lower alkylaminosulfonyl group,
a lowerialkylsufinyl group
an arylsulfinyl group,
an aminosulfinyl group,
an arylcarbonyl group,
an arylgroup which may be substituted,
a carbamoyl group,
an N-lower alkylcarbamoyl group,
an N,N-di-lower alkylaminocarbonyl group,
a lowerialkoxyiminomethyl group,
a hydroxyiminomethyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms, and
R represents a hydrogen atom or a group which may be hydrolyzed in organisms.
As used herein, the term xe2x80x9clower alkylxe2x80x9d or xe2x80x9clower alkoxyxe2x80x9d as a group or a part of a group means a straight chain or branched chain alkyl of alkyloxy having 1-6 carbon atoms, preferably 1-4 carbonatoms. Theexamples of the lower alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like. Further, the lower alkoxy includes by way of example methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, and the like.
The term xe2x80x9clower cycloalkylxe2x80x9d means monocyclic alkyl having 3-6 carbon atoms.
Further, the term xe2x80x9carylxe2x80x9d means an aromatic ring and aromatic polycyclic hydrocabon ring preferably phenyl or naphthyl.
The term xe2x80x9chalogenxe2x80x9d herein means fluorine, chlorine, bromine, or iodine.
In the formula (I), any one of R2, R3, R4, and R5 represents the bond to the 2-position on the carbapenem ring. The remaining three groups, which may be the same or different, respectively represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, a lower alkylthio group, an arylthio group, a C2-4 alkenyl group which may be substituted, a formyl group, a lower alkylcarbonyl group which may be substituted, a lower alkoxycarbonyl group, a lower alkylsulfonyl group, an arylsulfonyl group which may be substituted, an aminosulfonyl group, an N-loweralkylaminosulfonyl group which may be substituted, an N,N-di-lower alkylaminosulfonyl group which may substituted, an N-lower alkoxy-N-lower alkylaminosulfonyl group, a lower alkylsufinyl group, an arylsulfinyl group, an aminosulfinyl group, an arylcarbonyl group, an aryl group which may be substituted, a carbamoyl group, an N-lower alkylcarbamoyl group, an N,N-di-lower alkylaminocarbonyl group, a lower alkoxyiminomethyl group, a hydroxyiminomethyl group, or a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms.
According to the preferred embodiment of the present invention, the remaining three groups, which may be the same or different, respectively represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group which may be substituted, a lower cycloalkyl group which may be substituted, a lower alkylthio group, an arylthio group, a C2-4 alkenyl group which may be substituted, a formyl group, a lower alkylcarbonyl group which may be substituted, a lower alkylsulfonyl group, an arylsulfonyl group which may be substituted, an aminosulfonyl group, an N-loweralkylaminosulfonyl group which may be substituted, an N,N-di-lower alkylaminosulfonyl group which may be substituted, a lower alkylsufinyl group, an arylcarbonyl group, an aryl group which be substituted, a lower alkoxyiminomethyl group, a hydroxyiminomethyl group, or a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms. More preferably, the remaining three groups represent a hydrogen atom, a halogen atom, a cyano group, a lower alkyl group (in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a formylamino group, a lower alkylcarbonylamino group, acarbamoylgroup, andalower alkylsulfonylaminogroup), a lower cycloalkyl group which may be substituted by carbamoyl, a lower alkylthio group, an a rylthio group, a C2-4 alkenyl group (in which one or more hydrogen atoms on the alkenyl group may be substituted by a lower alkylcarbonyl group or a lower alkoxycarbonyl group), a formyl group, a lower alkylcarbonyl group (in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a lower alkylcarbonylamino group, N,N-di-lower alkylaminocarbonyl group, an (N-lower alkylamino)sulfonylamino group, an (N,N-di-lower alkylamino)sulfonylamino group and a lower alkylsulfonylamino group), a lower alkylsulfonyl group, anlarylsulfonyl group (in which one or more hydrogen atoms may beisubstituted by a lower alkyl group), an aminosulfonyl group, an N-loweralkylaminosulfonyl group (in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a lower alkoxy group, a hydroxy group, and an aryl group (in which one or more hydrogen atoms on the aryl group may be substituted by an amino group)), an N,N-di-lower alkylaminosulfonyl group, a lower alkylsufinyl group, an arylcarbonyl group, an aryl group which be substituted by a lower alkylcarbonyl group, a lower alkoxyiminomethyl group, a hydroxyiminomethyl group, or a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms (nitrogen, oxygen or sulfur atom).
In R2, R3, R4, R5 and R which represent lower alkyl, one or more hydrogen atoms on the lower alkyl may be substituted by halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, lower alkylsulfonylamino, and aryl. According to the preferred embodiment of the present invention, the substituent includes preferably halogen, hydroxy, amino, formylamino, lower alkylcarbonyl, carbamoyl and lower alkylsulfonyamino. The substituted alkyl includes for example aminomethyl, hydroxymethyl, 2-hydroxyethyl, carbamoylmethyl, 2-carbamoylethyl, 2-fluoroethyl, cyclopropylmethyl, 2-(N-methylcarbamoyl)ethyl, N,N-dimethylcarbamoylmethyl, 2-(N,N-dimethylcarbamoyl)ethyl, 2-aminosulfonylaminoethyl, aminosulfonylaminomethyl, 2-(aminosulfonylamino)ethyl, methoxymethyl, ethoxycarbonylmethyl, formylaminomethyl, methoxyiminomethyl, hydroxyiminomethyl, and benzyl.
In R2, R3, R4, and R5 which represent lower cycloalkyl, one or more hydrogen atoms on the cycloalkyl may be substituted by a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylarino, and aryl, more preferably carbamoyl.
Furthermore, in R2, R3, R4, and R5 which represent alkenyl, one or more hydrogen atoms on the alkenyl may be substituted, and the substituent includes for example a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, more preferably lower alkylcarbonyl and lower alkoxycarbonyl.
In R2, R3, R4, and R5 which represent lower alkylcarbonyl, one or more hydrogen atoms on the, group may be substituted, and the substituent includes for example a group selected from the group consisting of halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, lower alkylsulfonylamino, and aryl, more preferably halogen, hydroxy, amino, lower alkylcarbonylamino, N,N-di-lower alkylaminocarbonyl, (N-lower alkylamino)sulfonyl, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and lower alkylsulfonylamino.
In R2, R3, R4, and R5 which represent arylsulfonyl, one or more hydrogen atoms on the group may be substituted, and the substituent includes for example a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, and (N,N-di-lower alkylamino)sulfonylaminol more preferably lower alkyl.
Furthermore, in R2, R3, R4, and R5 which represent N-lower alkylaminosulfonyl, one or more hydrogen atoms on the group may be substituted, and the substituent includes for example a group selected from the group consisting of halogen, nitro, cyano, lower cycloalkyl, loweralkylthio, lower, alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower, alkylcarbonyl, arylcarbonyl, carboxyl, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl (in which one or more hydrogen atoms on the aryl may be substituted, and the substituent includes for example a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower allkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, and (N,N-di-lower alkylamino)sulfonylamino), more preferably lower alkoxy, hydroxy, and aryl (which may be substituted by amino).
Furthermore, in R2, R3, R4, and R5 which represent N-di-loweralkylaminosulfonyl, one or more hydrogen atoms on the group may be substituted, and the substituent includes for example a group selected from the group consisting of halogen, nitro, cyano, lowercycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl.
Furthermore, in R2, R3, R4, and R5 which represent aryl, one or more hydrogen atoms on the group may be substituted, and the substituent includes for example a group selected from the group consisting of lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamno)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, and (N,N-di-lower alkylamino)sulfonylamino, more preferably lower alkylcarbonyl.
Examples of a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms represented by R2, R3, R4, and R5 include thiazolyl, imidazolyl, oxazolyl, pyridyl, pyrrolyl, pyrazinyl, and pyrimidinyl, more preferably thiazolyl. On these groups, one or more hydrogen atoms may be substitutled, and the substituent includes for example lower alkyl, halogen, lower alkoxy, hydroxy, and amino.
R represents a group which may be hydrolyzed in organisms, preferably an ester residue Examples of the group include C1-10 alkyl, arylcarbonyloxy-lower alkyl group, aryl lower alkyloxy-lower-alkylcarbonyloxy-lower alkyl group, lower alkylcarbonyloxy-lower-alkyl, lower cycloalkylcarbonyloxy-lower-alkyl, lower cycloalkyl-lower-alkylcarbonyloxy-lower-alkyl, dicyclohexylmethylcarbonyloxy-lower-alkyl, adamantylcarbonyloxy-lower-alkyl, lower alkyloxycarbonyloxy-lower-alkyl, lower cycloalkyloxycarbonyloxy-lower-alkyl, (lower cycloalkyloxycarbonyloxy)(lower-cycloalkyl)methyl, lower-alkyl, adamantyloxlycarbonyloxy-lower-alkyl, 2-indanyloxycarbonyloxy-lower-alkyl, aryl-lower-alkyloxy carbonyloxy-lower-alkyl, aryloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted, 5-indanyloxycarbonyloxoy-lower-alkyl in which the aromatic ring maybesubstituted, 2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl, 3-phthalidyl in which the aromatic ring may be substituted, or 2-(3-phthalidylidene)ethyl in which the aromatic ring may be substituted.
According to another preferred embodiment of the present invention, R preferably represents
C1-10 alkyl,
arylcarbonyloxy-lower alkyl,
aryl lower alkyloxy-lower-alkylcarbonyloxy-lower alkyl group,
lower cycloalkyl-lower alkylcarbonyloxy-lower-alkyl,
dicyclohexylmethylcarbonyloxy-lower-alkyl,
adamantylcarbonyloxy-lower-alkyl
(lower cycloalkyloxycarbonylobxy)(lower-cycloalkyl)methyl,
lower cycloalkylethoxycarbonyloxy-lower-alkyl,
adamantyloxlycarbonyloxy-lower-alkyl,
2-indanyloxycarbonyloxy-lower-alkyl,
aryl-lower-alkyloxycarbonyloxy-lower-alkyl,
aryloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted, or
5-indanyloxycarbonyloxy-lower-alkyl.
According to another preferred embodiment of the present invention, R represents
benzoyloxymethyl,
1-(benzoyloxy)ethyl,
1-(2-methylbenzoyloxy)ethyl,
4-t-butylbenzoyloxymethy,
2,4,6-trimethylbenzoyloxymethyl,
4-(N,N-di-n-propylaminosulfony)benzoyloxymethly,
1-[4-(N,N-di-n-propylaminosulfony)benzoyloxymethly]ethyl,
2-naphtylcarbonyloxymethyl,
1-adamantylcarbonyloxymethyl,
1-(1-adamantylcarbonyloxy)ethyl,
cyclohexyl(cyclohexyloxycarbonyloxy)methyl,
(1R,2S,5R)-(l)-menthyloxycarbonyloxymethyl,
(1S,2R,5S)-(d)-menthyloxycarbonyloxymethyl,
1-[(cyclohexylethoxy)carbonyloxy]ethyl,
2-adamantyloxycarbonyloxymethyl,
1-(2-phenyl-1-ethyloxycarbonyloxy)ethyl,
1-(4-methylphenoxycarbonyloxy)ethyl,
1-(2-methylphenoxycarobonyloxy)ethyl,
1-(2-ethylphenoxycarobonyloxy)ethyl,
1-[2-(2-propyl)phenoxycarobonyloxy]ethyl,
1-(2,4-dimethylphenoxycarobonyloxy)ethyl,
1-(2,5-dimethylphenoxycarobonyloxy)ethyl,
1-(3,5-dimethylphenokycarobonyloxy)ethyl,
1-(2,3,5-trimethylphenoxycarobonyloxy)ethyl,
1-(2,6-dimethylphenoxycarobonyloxy)methyl,
2-methyl-1-(phenoxycarbonyloxy)-1-propyl,
1-(2-methoxyphenoxycarobonyloxy)ethyl,
(1-naphthoxycarbonyloxy)ethyl,
(indan-5-yl)oxyearbonyloxymethyl,
1-((indan-5-yl)oxycarbonyloxy)methyl, and
1-((indan-5-yl)oxycarbonyloxy)-1-propyl.
Examples of the substitulents on the 2-indanyloxycarbonyloxy-lower-alkyl, 5-indanyloxycarbonyloxy-lower-alkyl, 3-phthalidyl, and 2-(3-phthalidylidene)ethyl include lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower allkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, loweralkylcarbonyl arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower, alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, more preferably lower alkoxy, hydroxy, formylamino, and carbamoyl.
One or more hydrogen atoms on the alkyl group of lower-alklycarbonyloxy-lower-alkyl, lower-alkyloxycarbonyloxy-lower-alkyl, and 2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl represented by R may be substituted, and the substituents include for example halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, lower-alkylsulfonylamino, and aryl, more preferably lower alkoxy, lower-cycloalkyl, and aryl.
One or more hydrogen atoms on the aryl group of arylcarbonyoxy lower alkyl, aryl lower alkyloxy lower alkylcarbonyloxy lower alkyl, aryl lower alkyloxycarbonyloxy lower alkyl, aryloxycarbonyloxy lower alkyl represented by R may be substituted, and the substituents include for example lower alkyl, halogen, nitro, cyano, lower cycloalkyl, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aminosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, more preferably lower alkyl, lower alkoxy, lower-cycloalkyl, and aryl.
One or more hydrogen atoms on the cycloalkyl group of lower cycloalkylcarbonyloxy-lower-alkyl, lower cycloalkyl-lower-alkylcarbonyloxy-lower-alkyl, lower cycloalkyloxycarbonyloxy-lower-alkyl, (lower cycloalkyloxycarbonyloxy) (lower-cycloalkyl)methyl, and lower cycloalkyl lower alkyloxycarbonyloy lower alkyl represented by R may be substituted, and the substituents include for example lower alkyl, halogen, nitro, cyano, lower alkylthio, lower alkoxy, hydroxy, amino, N-lower alkylamino, formyl, lower alkylcarbonyl, arylcarbonyl, carboxy, lower alkoxycarbonyl, formylamino, lower alkylcarbonylamino, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylaminocarbonyl, aminosulfonyl, (N-lower alkylamino)sulfonyl, (N,N-di-lower alkylamino)sulfonyl, (N-lower alkylamino)sulfonylamino, aiinosulfonylamino, (N,N-di-lower alkylamino)sulfonylamino, and aryl, more preferably lower alkyl, lower alkoxy, and lower-cycloalkyl.
The preferred compounds of the formula (I) according to the present invention include those in which
R1 represents a hydrogen atom or a methyl group,
R2, R3, R4, and R5, either one of which represents the bonding to the 2-position on the carbapenem ring, and the other three of which may be the same or different, respectively represent
a hydrogen atom,
a halogen atom,
a cyano group,
a lower alkyl group which may be substituted,
a lower cycloalkyl group which may be substituted,
a lower alkylthio group,
an arylthio group,
a C2-4 alkenyl group which may be substituted,
a formyl group,
a lower alkylcarbonyl group which may be substituted,
a lower alkylsulfonyl group,
an arylsulfonyl group which may be substituted,
an aminosulfonyl group,
an N-loweralkylaminosulfonyl group which may be substituted,
an N,N-di-lower alkylaminosulfonyl group which may be substituted,
a lower alkylsufinyl group,
an arylcarbonyl group,
an aryl group which may be substituted,
a lower alkoxyiminomethyl group,
a hydroxyiminomethyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms.
The preferred compounds of the formula (I) according to the present invention include those in which R2 represents the bonding to the 2-position on the carbapenem ring. Among the compounds of formula (I) in which R2 represents the bonding to the 2-position on the carbapenem ring, the preferred compounds include those in which
R1 represents hydrogen or methyl,
R3, R4, and R5, which may be the same or different, and respectively represent
a hydrogen atom,
a hydrogen atom,
a cyano group,
a lower alkyl group in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a formylamino group, a lower alkylcarbonylamino group, a carbamoyl group, and a lower alkylsulfonylamino group,
a lower-cycloalkyl group which may be substituted by a carbamoyl group,
a lower alkylthio group,
an arylthio group,
a C2-4 alkenyl group in which one or more hydrogen atoms on the alkenyl group may be substituted by a lower alkylcarbonyl group or a lower alkoxy carbonyl group,
a formyl group,
a lower alkylcarbonyl group in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a lower alkylcarbonylamino group, N,N-di-lower alkylaminocarbonyl group, an (N-lower alkylamino)sulfonylamino group, an (N,N-di-lower alkylamino)sulfonylamino group and a lower alkylsulfonylamino group,
a lower alkyl sulfonyl group,
an aryl sulfonyl group in which one or more hydrogen atoms on the aryl group may be substituted by a lower alkyl group,
an aminosulfonyl group,
an N-lower alkylaminosulfonyl group in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a lower alkoxy group, a hydroxy group,
and an aryl group (in which one or more hydrogen atoms on the aryl group may be substituted by an amino group),
an N,N-di-lower alkylaminosulfonyl group,
a lower alkylsufinyl group,
an arylcarbonyl group,
an aryl group which may be substituted by a lower alkylcarbonyl group,
a lower alkoxyiminomethyl group,
a hydroxyiminomethyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur
Among the compounds, more preferred compounds include those in which
R1 represents methyl,
R3, R4, and R5, which may be the same or different, and respectively represent
a hydrogen atom,
a lower alkyl group which may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group,
an amino group, a formylamino group, a lower alkylcarbonylamino group, a carbamoyl group, a lower alkylsulfonylamino group, and
an aryl group,
a lower alkylthio group,
an arylthio group,
a lower alkylcarbonyl group which may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a lower alkylcarbonylamino group,
N,N-di-lower alkylaminocarbonyl group, an (N-lower alkylamino)sulfonylamino group, an (N,N-di-lower alkylamino)sulfonylamino group and a lower alkylsulfonylamino group,
a lower alkyl sulfonyl group,
an aryl sulfonyl group which may be substituted by a lower alkyl group,
an aminosulfonyl group,
an N-lower alkylaminosulfonyl group which may be substituted by groups selected from the group consisting of a lower alkoxy group,
a hydroxy group, group (which may be substituted by
an amino group),
an N,N-di-lower alkylaminosulfonyl group
a lower alkylsufinyl group,
a hydroxyiminomethyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms.
Another preferred compounds include those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 and R4 represent a hydrogen atom,
R5 represents a lower alkylthio group or a lower alkylsulfonyl group, and
R represents a hydrogen atom or a group which may be hydrolyzed in organisms. Among these compounds, more preferred compounds include those in which
R5 represents methylthio or methylsulfonyl.
Another preferred compounds include those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 and R4 represent a hydrogen atom,
R5 represents a lower alkylcarbonyl group (in which one or more hydrogen atoms on the alkyl group maybe substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a lower alkylcarbonylamino group,
N,N-di-lower alkylaminocarbonyl group, an (N-lower alkylamino)sulfonylamino group, an (N,N-di-lower alkylamino)sulfonylamino group and a lower alkylsulfonylamino group), a lower alkyl group substituted by a lower alkylcarbonylamino group, an N,N-di-lower alkylaminosulfonyl group, or a lower alkylsulfinyl group. Another preferred compounds include those in which
R1 represents methyl,
R2 represents the bonding to the 2-positionlon the carbapenem ring,
R3 and R4 represent a hydrogen atom,
R5 represents a lower alkyl group substituted by a lower alkylcarbonylamino group,
those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 and R4 represent a hydrogen atom,
R5 represents an N,N-di-lower alkylaminosulfonyl group,
those in which n
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 and R4 represent a hydrogen atom,
R5 represents an N,N-dimethylaminosulonyl group,
those in which
R1 represents methyl,
R2 represents the bonding to the 2-position, on the carbapenem ring,
R3 represents a hydrogen atom,
R4 represents a lower alkyl group,
R5 represents a lower alkylcarbonyl group which may be substituted by a hydroxy group,
those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 represents a hydrogen atom,
R4 represents a lower alkyl group, and
R5 represents a lower alkylsulfonyl group,
those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 represents a hydrogen atom,
R4 represents methyl, and,
R5 represents methylsulfonyl.
those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 and R4 represent a hydrogen atom, and
R5 represents a lower alkylsulfinyl group,
those in which
R1 represents methyl,
R2 represents the bonding to the 2-position on the carbapenem ring,
R3 and R4 represent a hydrogen atom, and
R5 represents methylsulfinyl group.
Another preferred compounds include those in which
R1 represents a hydrogen atom or a methyl group,
R2, R3, R4, and R5, except the one which represents the bonding to the 2-position on the carbapenem ring, which may be the same or different, and respectively represent
a hydrogen atom,
a lower alkyl group which be substituted,
an arylthio group,
a lower alkylcarbonyl group which may be substituted,
an arylsulfonyl group which may be substituted,
an N-loweralkylaminosulfonyl group which may be substituted,
an N,N-di-lower alkylaminosulfonyl group which may be substituted,
an N-lower alkoxy-N-lower alkylaminosulfonyl group,
a lower alkylsufinyl group,
a arylsulfinyl group,
an aminosulfinyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms,
those in which
R1 represents a hydrogen atom or a methyl group,
R2, R3, R4, and R5, except the one which represents the bonding to the 2-position on the carbapenem ring which may be the same or different, and respectively represent,
a hydrogen atom,
a lower alkyl group in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group,
an N-lower alkylamino group, a formylamino group, a lower alkylcarbonylamino group, a carbamoyl group, and a lower alkylsulfonylamino group,
an arylthio group,
a lower alkylcarbonyl group, in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a lower alkylcarbonlyamino group, N,N-di-lower alkylaminocarbonyl group, an (N-lower alkylamino)sulfonylamino group, an (N,N-di-lower alkylamino)sulfonylamino group and a lower alkylsulfonylamino group,
a arylsulfonyl group substituted by a lower alkyl group, an N-lower alkylaminosulfonyl group in which one or more hydrogen atoms on the alkyl group may be substituted by groups selected from the group consisting of a lower alkoxylgroup, a hydroxy gorup,
and an aryl group (which may be substituted by an amino group),
an N,N-di-lower alkylaminosulfonyl group
a lower alkylsufinyl group, or
a five- or six-membered aromatic heterocyclic ring having one or more hetero atoms selected from nitrogen, oxygen and sulfur atoms, and
those in which
R1 represents a hydrogen atom or a methyl group,
R2, R3, R4, and R5, except the one which represents the bonding to the 2-position on the carbapenem ring, which may be the same or different, and respectively represent
a hydrogen atom,
a lower alkyl group, in which one or more hydrogen atoms on the alkyl, group may be substituted by groups selected from the group consisting of a halogen atom, a nitro group, a cyano group, a lower cycloalkyl group, a lower alkylthio group, a lower alkoxy group, a hydroxy group, an amino group, an N-lower alkylamino group, a formyl group, a lower alkylcarbonyl group, an aryl carbonyl group, a carboxyl group, a lower alkoxycarbonyl group, a formylamino group, a lower alkylcarbonylamino group, a carbamoyl group an N-lower alkylcarbamoyl group, an N,N-di-lower alkylaminocarbonyl group, an aminosulfonyl group, an (N-lower alkylamino)sulfonyl group, an (N,N-di-lower alkylamino)sulfonyl group, an (N-lower alkylamino) sulfonylamino group, an aminosulfonylamino group, an (N,N-di-lower alkylamino)sulfonylamino group, a lower alkylsulfonylamino group and an aryl group, or
an arylthio group.
According to the preferred embodiment of the present invention, R preferably represents
C1-10 alkyl which may be substituted,
arylcarbonyloxy-lower-alkyl group which may be substituted, aryl lower alkyloxy-lower-alkylcarbonyloxy-lower alkyl group which may be substituted,
lower cycloalkyl-lower-alkylcarbonyloxy-lower-alkyl which may be substituted,
dicyclohexylmethylcarbonyloxy-lower-alkyl which may be substituted,
adamantylcarbonyloxy-lower-alkyl which may be substituted, (lower cycloalkyloxycarbonyloxy) (lower-cycloalkyl)methyl which may be substituted,
lower cycloalkyl-ethoxycarbonyloxy-lower-alkyl which may be substituted,
adamantyloxlycarbonyloxy-lower-alkyl which may be substituted,
2-indanyloxycarbonyloxy-lower-alkyl which may be substituted,
aryl-lower-alkyloxycarbonyloxy-lower-alkyl which may be substituted, or
5-indanyaoxycarbonyloxy-lower-alkyl which may be substituted.
According to another preferred embodiment of the present invention, R preferably represents
C1-10 alkyl,
arylcarbonyloxy-lower alkyl,
aryl lower alkyloxy-lower-alkylcarbonyloxy-lower alkyl group,
lower cycloalkyl-lower alkylcarbonyloxy-lower-alkyl,
dicyclohexylmethylcarbonyloxy-lower-alkyl,
adamantylcarbonyloxy-lower-alkyl,
(lower cycloalkyloxycarbonyloxy)(lower-cycloalkyl)methyl,
lower cycloalkylethoxycarbohyloxy-lower-alkyl,
adamantyloxycarbonyloxy-lower-alkyl,
indanyloxycarbonyloxy-lower-alkyl,
aryl-lower-alkyloxycarbonyloxy-lower-alkyl,
aryloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted, or
5-indanyloxycarbonyloxy-lower alkyl.
Among them, R preferably represents
C1-10 alkyl,
arylcarbonyloxy-lower-alkyl,
aryl lower alkyloxy-lower-alkylcarbonyloxy-lower-alkyl group,
lower cycloalkylcarbonyloxy-lower-alkyl,
lower cycloalkyl-lower-alkylcarbonyloxy-lower-alkyl,
dicyclohexylmethylcarbonyloxy-lower-alkyl,
adamantylcarbonyloxy-lower-alkyl,
lower alkyloxycarbonyloxy-lower-alkyl,
lower cycloalkyloxycarbonyloxy-lower-alkyl,
(lower cycloalkyloxycarbonyloxy)(lower cycloalkyl)methyl,
lower cycloalkyl-lower-alkyloxycarbonyloxy-lower-alkyl,
adamantyloxycarbonyloxy-lower-alkyl,
2-indanyloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted,
aryl-lower-alkyloxycarbonyloxy-lower-alkyl, aryloxycarbonyloxy-lower-alkyl,
5-indanyloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted. One or more hydrogen atoms on the alkyl group,
the lower cycloalkyl group or the aryl group on the above groups may be substituted.
The compound represented by the formula (I) according to the present invention can exist as a salt, and the preferred salt is a pharmacologically acceptable salt. Such a salt includes for example inorganic salts such as lithium, sodium, potassium, calcium, or magnesium salts, an ammonium salt, salts with organic bases such as triethylamine or diisopropylethylamine, salts with mineral acids such as hydrochloric acid, sulfuric aicd, phosphoric acid, or nitric acid, or salts with organic acids such as aceticacid, carbonic acid, citric acid, malic acid, oxalic acid, or methanesulfonic acid, preferably an inner salt, or sodium or potassium salt.
Specific examples of carbapenem derivatives represented by formula (I) according to the present invention include, but are not limited to
1. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-propionylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
2. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-propionylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
3. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-hydroxyiminomethylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a geometrical isomer derived from a starting compound as a low-polarity oxime isomer)
4. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxyiminomethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate (a geometrical isomer derived from a starting compound as a low-polarity oxime isomer)
5. Pivayloxymethyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-metholxyiminomethylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate (a geometrical isomer derived from a starting compound as a low-polaity oxime isomer)
6. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-pivaloylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
7. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-pivaloylimidazo[5,1]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
8. Sodium (5R,6S)-2-(7-acetyl-3-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
9. Pivaloyloxymethyl (5R,6S)-2-(7-acetyl-3-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
10. Sodium (1S,5R,6S)-2-[7-(2-formylaminopropionyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-metyl-1-carbapen-2-em-3-carboxylate (a high-polarity isomer)
11. Sodium (1S,5R,6S)-2-[7-(2-formylaminopropionyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a low-polarity isomer)
12. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-isobutyrylimidazo[5,1-b]thiazol-2-yl)-1-1-methyl-1-carbapen-2-em-3-carboxylate
13. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-isobutyrylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
14. Sodium (5R,6S)6-((1R)-1-hydroxyethyl)-2-(7-propionylimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate
15. Sodium (5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
16. Pivaloyloxymethyl (5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
17. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-isobutyrylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
18. Pivaloyloxymethyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-isobutyrylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
19. Sodium (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
20. Pivaloyloxymethyl (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
21. Sodium (1S,5R,6S)-2-(7-acetyl-3-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
22. Pivaloyloxymethyl (1S,5R,6S)-2-(7-acetyl-3-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxy-ethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
23. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
24. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-3-yl))-1-carbapen-2-em-3-carboxylate
25. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-37-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
26. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
27. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-propionylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
28. Pivaloyloxymethyl (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-propionylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
29. Pivaloyloxymethyl (5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-3-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
30. Sodium (1S,5R,6S)-2-(7-ethanesulfonylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
31. Sodium (1S,5R,6S)-6-((1R)-1-hlydroxyethy)-1-methyl-2-(7-N-methylsulfamoylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
32. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-N-methylsulfamoylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
33. Sodium (5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
34. Sodium (5R,6S)-2-(7-ethanesulfonylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
35. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-p-toluenesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
36. Sodium (5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
37. Sodium (1S,5R,6S)-2-(7-benzloylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
38. Sodium (5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-3-yl)-6-(1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
39. Sodium (5R,6S)-2-(7-benzoylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
40. Sodium (1S,5R,6S)-2-[7-[N-(4-aminobenzyl)sulfamoyl]imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
41. Sodium (1S,5R,6S)-2-(7-fluoroimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
42. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-[N-(2-hydroxyethyl)-N-methylsulfamoyl]imidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate
43. Sodium (1S,5R,6S)-2-(7-acetylaminoacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxymethyl-1-carbapen-2-em-3-carboxylate
44. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
45. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomners)
46. 1-(Ethoxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxy-ethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
47. 1-(Isopropoxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
48. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a
49. Cyclohexyloxycarbonyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
50. 3-Phthalidyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
51. 1-(Acetoxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
52. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
53. Sodium (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
54. Pivaloyloxymethyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
55. 1-(Acetoxy)ethyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
56. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
57. 3-Phthalidyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
58. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
59. 1-[(Cyclohexylmethoxy)carbonyloxy]ethyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
60. (1R,2S,5R)-(1)-Menthyloxycarbonyloxymethyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
61. 1-(Cyclohexyloxycarbonyloxy)-n-propyl (1S,5R,6S)-2-(7-N-acetylaminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
62. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
63. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
64. 1-(Acetoxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
65. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazod[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
66. 3-Phthalidyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture, of diastereomers)
67. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
68. 1-[(Cyclohexylmethoxy)carbonyloxy]ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
69. (1-Methylcyclohexan-1-yl)carbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
70. 1-(Cyclohexyloxycarbonyloxy)-n-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
71. Sodium (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-;
72. Pivaloyloxymethyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
73. 1-(Acetoxy)ethyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
74. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
75. 3-Phthalidyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
76. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
77. (1-Methylcyclohexan-1-yl)carbonyloxymethyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
78. 1-[(Cyclohexylmethoxy)carbonyloxy]ethyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
79. 1-(Cyclohexyloxycarbonyloxy)-n-propyl (1S,5R,6S)-2-(7-hydroxyacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
80. Sodium (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)-acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
81. Pivaloyloxymethyl (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
82. (1-Methylcyclohexan-1-yl)carbonyloxymethyl (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
83. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-2-[7-(N,N-dimethyldarcamoyl)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
84. 3-Phthalidyl (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
85. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)acetylimidazo-[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
86. 1-[(Cyclohexylmethoxy)carbonyloxy]ethyl (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
87. 1-(Cyclohexyloxycarbonyloxy)-n-propyl (1S,5R,6S)-2-[7-(N,N-dimethylcarbamoyl)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
88. Sodium (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em -3-carboxylate
89. (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylatepivaloyloxymethyl
90. (1-Methylcyclohexan-1-yl)carbonyloxymethyl (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
91. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
92. 3-Phthalidyl (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
93. (5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
94. 1-[(Cyclohexylmethoxy)carbonyloxy]ethyl (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em -3-carboxylate (a mixture of diastereomers)
95. ((Cyclohexyloxycarbonyloxy)-n-propyl (1S,5R,6S)-2-[7-(N,N-dimethylsulfamoyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
96. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methoxycarbonylimidazo[5,1-b ]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
97. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(N-methoxy-N-methylsulfamoyl)imidazo[5, i1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate
98. Sodium (1S,5R,6S)6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-trifluoroacetylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
99. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-sulfamoylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate 100. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-(E)-methoxycarbonylvinyl)imidazo[5,1-b]thiazol-2-yl]1-methyl-1-carbapen-2-em-3-carboxylate
101. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(2-(Z)-methoxycarbonylvinyl)imidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate
102. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethy)-1-methyl-2-[7-(thiazol-4-yl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate
103. Sodium (1S,5R,6S)-2-(7-hydroxyacetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
104. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
105. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
106. Sodium (5R,6S)-2-(7-hydroxyacetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxy-ethyl)-1-carbapen-2-em-3-carboxylate
107. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
108. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylaminoacetylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
109. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
110. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-[7-(methanesulfonylaminomethyl)imidazo[5,1-b]thiazol-2-yl]-1-methyl-1-carbapen-2-em-3-carboxylate
111. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
112. Sodium (5R,6S)-2-(7-dimethylaminosulfonyl-imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxy-ethyl)-1-carbapen-2-em-3-carboxylate
113. Sodium (5R,6S)-2-(7-aminosulfonylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
114. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-((E)-3-oxo-1-buten-1-yl)imidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate
115. Sodium (1S,5R,6S)-2-(7-formyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
116. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
117. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
118. Sodium (5R,6S)-2-[7-(N,N-dimethylaminosulfonylamino)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
119. Sodium (1S,5R,6S)-2-[7-(N,N-dimethylaminosulfonylamino)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
120. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
121. Sodium (1S,5R,6S)-2-(7-aminoacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
122. Sodium (1S,5R,6S)-2-(7-aminiomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
123. Sodium (1S,5R,6S)-2-[7-(2-aminoethanesulfonylamino)acetylimidozo[5,1-b]thiazol-2-yl]-6-((1R)-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
124. Sodium (5R,6S)-2-[7-(2-aminoethanesulfonyl-amino)acetylimidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
125. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
126. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(5-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
127. Sodium (1S,5R,6S)-2-[5,1-bis (methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
128. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-phenylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
129. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methylthioimidazo[5,1-b]thiazol-3-yl)-1-carbapen-2-em-3-carboxylate
130. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-phenylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
131. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(3-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
132. Sodium (1S,5R,6S)-2-(7-ethylthioimidazo-[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
133. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
134. Sodium (5R,6S)-2-(7-ethylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
135. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-methyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
136. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfinyl-5-methylthioimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
137. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
138. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-phenylimidazo[5,1-b]thiazol-2-yl)-71-carbapen-2-em-3-carboxylate
139. Sodium (5R,6S)-2-(7-aminoacetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
140. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methanesulfinylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
141. Sodium (1S,5R,6S)-2-(5,7-dimethanesulfinyl-imidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxy-ethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
142. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(5-methanesulfinyl-7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
143. Sodium (1S,5R,6S)-2-[5,7-bis (methane-sulfonyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
144. Sodium (5R,6S)-2-(3-aminomethylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
145. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(3-hydroxymethylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
146. Sodium (5R,6S)-2-[5,7-bis(methylthio)-imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
147. Sodium (1S,5R,6S)-2-(5-acetyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
148. Sodium (1S,5R,6S)-2-[3,7-bis (methylthio)-imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl-1-carbapen-2-em-3-carboxylate
149. Sodium (1S,5R,6S)-2-(5-acetyl-7-methanesulfonylimidazo[5,1-b]thiazol)-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
150. Sodium (1S,5R,6S)-2-(5-bromo-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
151. Sodium (5R,6S)-2-(5-acetyl-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
152. Sodium (1S,5R,6S)-2-(5-cyano-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
153. Sodium (5R,6S)-2-[3,7-bis (methylthio)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
154. Sodium (1S,5R,6S)-2-(5-chloro-7-methylthioinidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
155. Sodium (5R,6S)-2-(5-cyano-7-methylthioimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-carbapen-2-em-3-carboxylate
156. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-[7-(1-propyl)thioimidazo[5,1-b]thiazol-2-yl]-1-carbapen-2-em-3-carboxylate
157. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-(1-propyl)thioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
158. Sodium (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-isopropylthioimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbepen-2-em-3-carboxylate
159. Sodium (5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-isopropylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
160. 1-Methylcyclohexylcarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
161. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
162. Cyclohexyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
163. 3-Phthalidyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methiinesulfonyl-5-methyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
164. 5-Methyl-2-oxo-1,3-dioxolen-4-ylmethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
165. (Z)-2-(3-Phthalidylidene)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-5-methylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
166. 1-(Ethoxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
167. 1-(Cyclohexyloxycarbohyloxy)ethyl (1S,5R,6S)-2-(7-acetyl-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
168. Cyclohexyloxycarbonyloxymethyl (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
169. 3-Phthalidyl (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
170. 5-Methyl-2-oxo-1,3-dioxolen-4-ylmethyl (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
171. Cyclopentyloxycarbonyloxymethyl (1S,5R,6S)-2-(7-acetyl-5-methylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
172. 1-(Pivaloyloxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
173. 1-Methylcyclohexylcarbonyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
174. Cyclohexylcarbonyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
175. 1-(Cyclohexylcarbonyloxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
176. Hexanoyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
177. 2-Ethylbutyryloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
178. Cyclopentyloxycarbonyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-carbapen-2-em-3-carboxylate
179. 1-(3-Pentyloxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
180. 3-Pentyloxycarbonyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
181. Cyclohexylmethoxycarbonyloxymethyl (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
182. 1-(Isobutyryloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
183. 1-(Pivaloyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
184. Hexanoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
185. Cyclohexylcarbonyloxethyl (1S5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
186. Cyclohexylacetoxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
187. Dicyclohexylacetoxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
188. 1-(1-Methylcyclohexylcarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
189. 1-Adamantylcarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
190. 1-(1-Adamantylcarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
191. 1-(Benzoyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
192. 4-(2-Propyl)benzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
193. 4-n-Butylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
194. 4-Phenylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
195. 4-t-Butylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
196. 1-(4-t-Butylbenzoyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
197. 2,4,6-Trimethylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
198. 1-(2-Propyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
199. 1-(2-Butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
200. 1-(3-Pentyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
201. 1-(1-Butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
202. 4-Heptyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
203. 1-(4-Heptyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
204. 1-(1-Pentyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
205. 1-(4-Methyl-1-pentyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
206. 5-Nonyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
207. 1-(5-Nonyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
208. 1-(2,2-Dimethyl-1-propyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
209. 1-(3,3-Dimethyl-2-butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
210. Cyclohexylmethoxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfoniylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
211. 1-(Cyclohexylmethoxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
212. 1-(Dicyclohexylmethoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
213. Cyclohexyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
214. 1-(Cyclohexyloxycarbonyloxy)-2-methyl-1-propyl (1S,5R,6S)-6-((1R)-1-hyoroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
215. Cyclohexyl(cyclohexyloxycarbonyloxy)methyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulifonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
216. (1R,2S,5R)-(l)-menthyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
217. 1-((1R,2S,5R)-(1)-Menthyloxycarbonyloxy)-ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
218. (1S,2R,5S)-(d)-Menthyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
219. (1S,2R,5R)-isomenthyloxycarbpnyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
220. (1S,2S,5R)-Neomenthyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
221. 3,3,5,5-Tetramethylcyclohexyloxycarbonyloxy-methyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
222. 2-Adamantyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
223. 1-((Indan-2-yl)oxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
224. 1-(2-Methylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
225. 1-(2-Ethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
226. 1-(3-Methylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
227. 1-(4-Methylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
228. 1-(2,6-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
229. 1-(2,4-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
230. 1-(3,5-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
231. 1-(2,4,6-Trimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulilfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
232. 1-(4-t-Butylphenoxycarbonyloxy)ethyl-(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
233. (Indan-5-yl)oxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
234. 1-((Indan-5-yl)oxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimildazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
235. 1-((Indan-5-yl)oxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
236. Ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
237. 2-Propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
238. 1-Decyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonylimidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
239. (Z)-2-(3-Phthalidylidene)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-2-(7-methanesulfonyl-imidazo[5,1-b]thiazol-2-yl)-1-methyl-1-carbapen-2-em-3-carboxylate
240. Acetoxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
241. 1-(Acetoxy)ethyl (1S,5R,6S)-6-((R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
242. 1-(Isobutyryloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
243. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
244. 1-(Pivaloyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
245. 2-Ethylbutyryloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
246. 1-(2-Ethylbutyryloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
247. Cyclohexylcarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
248. 1-(Cyclohexylcarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
249. Dicyclohexylacetoxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
250. 1-Adamantylcarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
251. 1-(1-Adamantylcarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxlate (a mixture of diastereomers)
252. 3-Phthalidyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
253. Benzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
254. 1-(Benzoyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
255. 2-Methylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carbolxylate
256. 1-(2-Methylbenzoyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture diastereomers)
257. 4-Methylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
258. 4-(2-Propyl)benzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
259. 2,4-Dimethylbenzoyloxymethyl (1S,5R,6S)-6-(1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
260. 2,4,6-Trimethylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
261. 1-(Benzyloxyacetoxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
262. 1-(Ethoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carbokylate (a mixture of diastereomers)
263. 2-Propyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
264. 1-(2-Propyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
265. 1-(1-Propyloxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthiimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxyiate (a mixture of diastereomers)
266. 2-Methyl-1-(2-propyloxycarbonyloxy)-1-propyl
(1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
267. 1-1-Propyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
268. 3-Pentyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
269. 1-(3-Pentyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carbolxylate (a mixture of diastereomers)
270. 1-(1-Butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthiolimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
271. 4-Heptyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
272. 1-(4-Heptyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio iniidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
273. 1-(3-Methyl-1-butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
274. 1-(1-Pentyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
275. 1-(4-Methyl-1-pentyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
276. 5-Nonyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
277. 1-[3-(2,4-Dimethyl)pentoxycarbonyloxy]ethyl (1S,5R,6S)-6-((R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
278. 1-(2,2-Dimethyl-1-propyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
279. 1-(33-Dimethyl-2-butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
280. 1-(2-Cyclohexyl-1-ethyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
281. 1-(2-Phenyl-1-ethyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-metlhylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
282. Cyclohexyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
283. 1-(Cyclohexyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
284. 1-(Cyclohexyloxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
285. 1-(Cyclohexyloxycarbonyloxy)-2-methyl-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
286. Cyclohexyl(cyclohexyloxycarbonyloxy)methyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
287. 2-Adamantyloxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
288. Phenoxycarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo-[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
289. 1-(Phenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
290. 1-(Phenoxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
291. 1-(2-Methylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
292. 1-(2-Ethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
293. 1-(2-Methoxyphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
294. 1-(3-Methylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
295. 1-(3-Methoxyphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-((7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
296. 1-(4-Methylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
297. 1-(4-Ethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
298. 1-(4-Methoxyphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxy late (a mixture of diastereomers)
299. 1-(2,6-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6R)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
300. 1-(2,4-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
301. 1-(2,5-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
302. 1-[2-Methyl-5-(2-propyl)phenoxycarbonyl]-ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
303. 1-(3,5-Dimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
304. 1-(2,4,6-Trimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
305. 1-((Indan-5-yl)oxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers) (a mixture of diastereomers)
306. 1-((Indan-5-yl)oxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
307. 1-Heptyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
308. 5-Methyl-2-oxo-1,3-dioxolen-4-ylmethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
309. (Z)-2-(3-Phthalidylidene)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
310. 1-(1,1-Dimethyl-1-butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
311. 1-(3,3-Dimethyl-1-butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
312. 1-(2-Methoxybenzoyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
313. 3,5-Dimethylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
314. 1-[2-(2-Propyl)phenoxycarbonyloxy]ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
315. (2,2-Dimethyl-1-propyloxycarbonyloxy)methyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
316. 1-2-Ethyl-1-butyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-ethyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
317. 1-(3-Methyl-1-butyloxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
318. 1-(2,6-Dimethylphenoxycarbonyloxy)methyl 1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
319. 1-(2,3,5-Trimethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
320. 2-Naphthylcarbonyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
321. 2,5-Dimethylbenzoyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthio-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
322. Cyclohexyloxycarbonyloxymethyl (1S,5R,6S)-2-[7-(N,N-dimethylaminosulfonyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate
323. 2-Methyl-1-(phenoxycarbonyloxy)-1-propyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
324. 1-(1-Naphthoxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
325. 1-[2-(1-Propyl)phenoxycarbonyloxy]ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
326. (2-Ethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-2-(7-etylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
327. (2-Ethylphenoxycarbonyloxy)ethyl (1S,5R,6S)-2-[7-(N,N-dimethylaminosulfonyl)imidazo[5,1-b]thiazol-2-yl]-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
328. Pivaloyloxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylsulfinyl-imidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
329. 1-1-(2-Benzyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
330. 1-(2-Methyl-1-propyloxycarbonyloxy)ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers)
331. 4-(N,N-di-n-propylaminosulfonyl)benzoyl-oxymethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate
332. 11-[4-(N,N-Di-n-propylaminosulfonyl)benzoyl-oxy]ethyl (1S,5R,6S)-6-((1R)-1-hydroxyethyl)-1-methyl-2-(7-methylthioimidazo[5,1-b]thiazol-2-yl)-1-carbapen-2-em-3-carboxylate (a mixture of diastereomers).
The compounds according to the present invention can be prepared by a variety of methods. The preferred preparation methods are shown below.
The compound of the formula (I) in which R is hydrogen can be prepared according to the following reaction scheme. 
wherein
R1, R2, R3, R4 and R5 have the same meaning as defined in the formula (I), R6 represents hydrogen or a hydroxyl protecting group such as t-butyldimethylsilyl, trimethylsilyl, triethylsilyl, 4-nitrobenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, R7 represents a carboxyl protecting group such as 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl, t-butyldimethylsilyl,
R8 represents lower alkyl, preferably n-butyl and methyl,
R9, R10, R11, and R12 have the same meaning as R1, R2, R3, R4 and R5 or represent a protected group thereof in which a functional group such as hydroxy, amino, carboxy, and hydroxyimino is protected by a conventional protective group.
The compound of the formula (II) can be prepared by the ordinary method, and the tin compound of the formula (IV) can be prepared by a method described below.
In the first step, the compound of the formula (II) can be converted into the compound of the formula (III) by the following method. The compound (III) can be prepared by reacting the compound of the formula (II) with one (1) equivalent or an excessive amount of anhydrous trifluoromethanesulfonic acid in the presence of an organic base, preferably diisopropylethylamine in an amount of one (1) equivalent or an excessive amount to anhydrous trifluoromethanesulfonic acid in an inert solvent such as acetonitrile, tetrahydrofuran, dichloromethane, and toluene, and the mixed solvent thereof at a temperature of xe2x88x9250xc2x0 C.-+50xc2x0 C. for 10 minutes-24 hours, and then subjecting the reaction mixture to the usual purification procedure.
In the second step, the compound of the formula (III) can be converted into the compound of the formula (V) by the following method. The compound of the formula (V) can be prepared by reacting the compound of the formula (III) with one (1) equivalent or an excessive amount of the compound of the formula (V) in the presence of 0.001-1 equivalent of a palladium catalyst such as tetrakis(triphenylphosphine)palladium(0), tris(dibenzylideneacetone)-dipalladium(0) or tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct, 0.01-1 equivalent of a phosphine ligand such as triphenylphosphine, tri-2-furylphosphine, or tri-2-thienylphosphine, tris(2xe2x80x2,4,6-trimethoxyphenyl)phosphine, and 1-10 equivalents of an additive such as zinc chloride, lithium chloride, or cesium fluoride alone or in combination thereof in an inert solvent such as tetrahydrofuran, dimethoxyethane, dioxane, acetonitrile, acetone, ethanol, dimethylsulfoxide, sulfolane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidinone, or hexamethylphosphoric triamide, or a mixed solvent thereof at 0xc2x0 C.-100xc2x0 C. for 10 minutes-7 days, and then, subjecting the reaction mixture to the ordinary post-treatment.
In the third step, the protective groups R6 and R7 or the protective groups on R9, R10, R11, and R12 in the compound of the formula (V) can be removed by the deprotection reaction in one step or plural steps depending on the kinds of the protective groups to obtain the compound of the formula (I) according to the present invention. The deprotection reactions, which depend on the kinds of the protective groups R6 and R7 or the protective groups on R9, R10, R11, and R12 used, can be carried out according to the usual methods generally known in the art. When either one or both of the protective groups can be removed under the acidic condition, a mineral acid such as hydrochloric acid, an organic acid such as oxalic acid, acetic acid or citric acid, or a Lewis acid such as aluminium chloride is used. When the protective groups is removed under a reducing condition, catalytic reduction with a variety of catalysts, or a metallic reducing agent such as zinc or iron is used. When R6 is a silyl type protective group such as a t-butyldimethylsilyl group, a trimethylsilyl group or a triethylsilyl group, it can be easily removed with use of a fluorine ion reagent such as tetrabutylammonium fluoride. When R6 is an allyloxycarbonyl group and R7 is an allyl group, the protective groups can be easily removed with use of a variety of palladium complexes such as tetrakis(triphenylphosphine)palladium(0).
The compound of the formula (V) in which at least one of R9, R10, R11, and R12 is lower alkylthio can be converted to the compound of formula (Vxe2x80x2) in which the lower alkylthio group is converted to lower alkylsulfonyl or lower alkylsulfinyl according to the following reaction. 
in which
R1 has the same meaning as defined in the formula (I),
R6, R7, R9, R10, R11 and R12 have the same meaning as defined in the formula (V) in Process (1) above, R13, R14, R15 and R16 have the same meaning as R9, R10, R11 and R12, provided that at least one of R9, R10, R11 and R12 represents lower alkylthio and at least one of R13, R14, R15 and R16 represents lower alkylsulfonyl or lower alkylsulfinyl.
The compound of the formula (V) can be converted into the compound of the formula (Vxe2x80x2) by reacting the compound of the formula (V) with one (1) equivalent or an excessive amount of an oxygenation agent (e.g. OXONE by Du Pont, m-chloroperbenzoic acid) in an inert solvent such as THF, dioxane, dichloromethane, chloroform or water or a mixed solvent thereof at a temperature of xe2x88x9250xc2x0 C.-+100xc2x0 C. for 10 minutes-7 days, and then subjecting the reaction mixture to the usual purification procedure.
The compound of the formula (Vxe2x80x2) can be concerted to the compound of the formula (I) in the same manner as in the third step of Process (1).
The compound of the formula (I) thus obtained can be isolated and purified by crystallization or by chromatography with a nonionic macro-high porous resin, gel filtration with Sephadex or the like, or reverse phase silica gel column chromatography.
The compounds of the formula (I) in which R represents an ester hydrolizable in organisms can be prepared by converting the compounds represented by the formula (I) in which R is hydrogen into the ester derivatives. 
in which
R1, R2, R3, R4, and R5 have the same meanings as defined in the formula (I),
R17 represents C1-10 alkyl,
arylcarbonyloxy-lower alkyl group, aryl lower alkyloxy-lower-alkylcarbonyloxy-lower alkyl group, lower alkylcarbonyloxy-lower-alkyl, lower cycloalkylcarbonyloxy-lower alkyl, lower cycloalkyl-lower-alkylcarbonyloxy-lower-alkyl, dicyclohexylmethylcarbonyloxy-lower-alkyl, adamantylcarbonyloxy-lower-alkyl, lower alkyloxycarbonyloxy-lower-alkyl, lower cycloalkyloxycarbonyloxy-lower-alkyl, (lower cycloalkyloxycarbonyloxy)(lower-cycloalkyl)methyl, lower cycloalkyl-lower-alkyloxycarbonyloxy-lower-alkyl, adamantyloxlycarbonyloxy-lower-alkyl, 2-indanyloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted, aryl-lower-alkyloxycarbonyloxy-lower-alkyl, aryloxycarbonyloxy-lower-alkyl in which the aromatic ring may be substituted, 5-indanyloxycarbonyloxoy-lower-alkyl in which the aromatic ring may be substituted, 2-oxo-5-lower alkyl-1,3-dioxolen-4-ylmethyl, 3-phthalidyl in which the aromatic ring may be substituted, or 2-(3-phthalidylidene)ethyl in which the aromatic ring may be substituted, X represents a leaving group such as Cl, Br, I, xe2x80x94OSO2CF3, xe2x80x94OSO2CH3, or xe2x80x94OSO2PhCH3.
The compound of the formula (Ixe2x80x2) can be prepared by reacting the compound of the formula (I) with an alkyl halide R17xe2x80x94X in the presence of one (1) equivalent or an excessive amount of a base at a temperature of xe2x88x9270-+50xc2x0 C., preferably xe2x88x9230xc2x0 C.-+20xc2x0 C. for 10 minutes 24 hours.
The base usable in the reaction includes for example organic bases such as diisopropylethylamine, diazabicyclo[2,2,2]undecene and 2,6-lutidine, and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate and cesium carbonate.
The alkyl halide R17xe2x80x94X includes for example
pivaloyloxymethyl iodide,
1-(pivaloyloxy)ethyl iodide,
isobutyryloxymethyl iodide,
1-(isobutyryloxy)ethyl iodide,
acetoxymethyl iodide,
1-(acetoxy)ethyl iodide,
(1-methyl cyclohexan-1-yl)carbonyloxymethyl iodide,
benzoyloxymethyl iodide,
1-(benzoyloxy)ethyl iodide,
1-(2-methylbenzoyloxy)ethyl iodide,
4-t-butylbenzoyloxymethy iodide,
2,4,6-trimethylbenzoyloxymethyl iodide,
4-(N,N-di-n-propylaminosulfonyl)benzoyloxymethyl iodide,
1-[4-(N,N-di-n-propylaminosulfonyl)benzoyloxy]ethyl iodide,
2-naphtylcarbonyloxymethyl iodide,
1-adamantylcarbonyloxymethyl iodide,
1-(1-adamantylcarbonyloxy)ethyl iodide,
cyclohexyloxycarbonyloxymethyl iodide,
1-(cyclohexyloxycarbonyloxy)ethyl iodide,
1-(cyclohexyloxycarbonyloxy)-1-propyl iodide,
1-[(cyclohexylmethoxy)carbonyloxy]ethyl iodide,
1-[(cyclohexylethoxy)carbonyloxy]ethyl iodide,
1-(ethoxycarbonyloxy)ethyl iodide,
1-[(2-methylcyclohexan-1-yl)oxycarbonyloxy]ethyl iodide,
cyclopentyloxycarbonyloxymethyl iodide,
1-(isopropyloxycarbonyloxy)ethyl iodide,
(1R,2S,5R)-(1)-menthyloxycarbonyloxymethyl iodide,
(1S,2R,5S)-(d)-menthyloxycarbonyloxymethyl iodide,
2-adamantyloxycarbonyloxymethyl iodide,
1-(2-phenyl-1-ethyloxycarbonyloxy)ethyl iodide,
phenyloxycarbonyloxymethyl iodide,
1-(phenyloxycarbonyloxy)ethyl iodide,
1-(4-methylphenoxycarbonyloxy)ethyl iodide,
1-(2-methylphenoxycarbonyloxy)ethyl iodide,
1-(2-ethylphenoxycarbonyloxy)ethyl iodide,
1-[2-(2-propyl)phenoxycarobonyloxy]ethyl iodide,
1-(2,4-dimethylphenoxycarobonyloxy)ethyl iodide,
1-(2,5-dimethylphenoxycarbonyloxy)ethyl iodide,
1-(3,5-dimethylphenoxycarbonyloxy)ethyl iodide,
1-(2,3,5-trimethylphenoxycarbonyloxy)ethyl iodide,
1-(2,6-dimethylphenoxycarbonyloxy)methyl iodide,
2-methyl-1-(phenoxycarbonyloxy)-1-propyl iodide,
1-(2-methoxyphenoxycarbonyloxy)ethyl iodide,
1-(1-naphthoxycarbonyloxy)ethyl iodide,
1-(indan-5-yl)oxycarbonyloxymethyl iodide,
1-((indan-5-yl)oxycarbonyloxy)methyl iodide,
1-((indan-5-yl)oxycarbonyloxy)-1-propyl iodide,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl bromide,
3-phthalidyl bromide,
4-(Z)-2-(3-phthalidylidne)ethyl bromide.
The inert solvent usable in the reaction includes N,N-dimethylforamide, N,N-dimethylacetamide N,N-diethylformamide, N,N-diethylacetamide, N-methylpyrrolidinone, N,N-dimethylimidazolidinoen, dimethylsulifoxide, sulfolane, acetonitrile, acetone, ethyl acetate, tetrahydrofuran, 1,4-dioxane, diethyl ether, anisole, dichloromethane, 1,2-dichloroethane, chloroform, toluene, benzene, hexamethylphosphoric triamide, methanol, and ethanol.
The compound (Ixe2x80x2) thus obtained can be isolated and purified by precipitation, crystallization, gel filtration with Sephadex, or silica gel chromatography.
The compound of the formula (IV) used in the above described reaction can be prepared by the following method. 
in which
R9, R10, R11, and R12, either one of which is M or R83SN, and the remaining three, which may be the same or different, have the same meanings as R2, R3, R4, and R5 or represent a protected group thereof in which a functional group such as hydroxyl, amino, carboxy, and hydroxyimino is protected by a conventional protective group,
R8 represents lower alkyl, preferably n-butyl or methyl,
M represents Li, MgCl, MgBr or MgI, and
Z represents Cl, Br, I or xe2x80x94OSO2CF3.
The compound of the formula (VI) used can be prepared according to the method described in WO98/023623.
The compound of the formula (VI) can be converted into the compound of the formula (IV) by the following method. The compound of the formula (IV) can be prepared by reacting the compound of the formula (VI) in an inert solvent such as tetrahydrofuran, diethyl ether, 1,4-dioxane, anisole, dimethoxyethane, dichloromethane or toluene solely or in combination thereof with R83SNZ in a proportion of one (1) equivalent or an excessive amount to the compound of the formula (VI) at a temperature of xe2x88x92100xc2x0 C.-+50xc2x0 C. for 15 minutes-24 hours, and then subjected to the usual post-treatment.
The compound of the formula (IV) thus obtained can be isolated and purified by crystallization or by chromatography with a nonionic macro-high porous resin, gel filtration with Sephadex, or the like, or reverse phase silica gel column chromatography.
The compound according to the present invention has wide and strong anti-microbial activities against Gram-positive and Gram-negative bacteria, and exhibits strong anti-microbial activities against MRSA, PRSP, enterococci, influenza and xcex2-lactamase producing bacteria as well. Furthermore, it has low toxicity and stable to DHP-1. Thus, the compound according to the present invention can be used for the treatment of infections caused by various pathogenic bacteria in animals including human
The compound of the formula (I) in which R represents a group hydrolyzable in organisms above all can be advantageously administered orally because of its excellent oral absorption property.
The pharmaceutical composition comprising the compound according to the present invention and a pharmacologically acceptable salt and ester thereof as an effective ingredient can be adminitered orally or parenterally by the adminitration routes including intravenous injection, intramuscular injection, or subcutaneous, rectal or percutaneous administration to human beins and the other animals. Thus, the pharmaceutical composition comprising the compound according to the present invention as an effective ingredient can be formed into appropriate dosage forms depending on its administration routes, and specifically prepared primarily into any one of the preparation forms including injections such as intravenous injection and intramuscular injection, preparations for oral administration such as capsules, tablets, granules, powder, pills, particulates, troches, preparations for rectal administration, and fatty suppositories. These preparations can be prepared by the usual methods with ordinarily used excipients, fillers, binding agents, humidifiers, disintegrants, surface active agents, lubricants, dispersants, buffers, storing agents, dissolution aids, preservatives, flavoring agents, analgesic agents, stabilizing agents, and the like. Such non-toxic additives which can be used include for example lactose, fructose, glucose, starch, gelatin, magnesium carbonate, synthetic magnesium silicate, talc, magnesium stearate, methylcellulose or a salt thereof, gum arabic, polyethylene glycol, syrup, petrolatum, glycerol, ethanol, propylene glycol, citric acid sodium chloride, sodium sulfite, sodium phosphate, and the like. The dosage amount is appropriately determined in consideration of the dosage route, and the age, sex and condition of a patient, and the preparation may be administered for the treatment of infections usually in an amount of about 25 mg-2000 mg, preferably 50 mg-1000 mg per day for adult in one or several portions.